Activatable fluorescent molecular imaging of peritoneal metastases following pretargeting with a biotinylated monoclonal antibody.

Abstract

Optical probes that yield high target-to-background ratios are necessary to detect microfoci of cancer that would otherwise escape detection with white light imaging. Target-specific activation of the optical signal at tumor foci is one mechanism by which high target and low background signal can be achieved. Here, we describe a two-step activation process in which the tumors are first pretargeted with a nonfluorescent biotinylated monoclonal antibody [cetuximab (Erbitux) targeting human epidermal growth factor receptor type 1 (HER1)]. Following this, a second agent, neutravidin-BODIPY-FL fluorescent conjugate, is given and binds to the previously targeted antibody, resulting in an approximately 10-fold amplification of the optical fluorescence signal, leading to high tumor-to-background ratios. Spectral fluorescence imaging was done in a mouse model of peritoneal metastasis using a HER1-overexpressing cell line (A431) after pretargeting with biotinylated cetuximab and 3 h after administration of neutravidin-conjugated BODIPY-FL. Both aggregated tumors as well as small cancer implants were clearly visualized in vivo. For lesions approximately 0.8 mm or greater in diameter, the spectral fluorescence imaging had a sensitivity of 96% (178 of 185) and a specificity of 98% (188 of 191). This two-step activation paradigm (pretargeting followed by neutravidin-biotin binding with an attached activatable fluorophore) could be useful in tumor-specific molecular imaging of various targets to guide surgical resections.

• Authors: Yukihiro Hama, Yasuteru Urano, Yoshinori Koyama, Peter L Choyke, Hisataka Kobayashi
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 8 Pg. 3809-17 (Apr 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17440095 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Boron Compounds
• Fluorescent Dyes
• Immunoconjugates
• neutravidin
• Avidin
• EGFR protein, human
• ErbB Receptors
• Cetuximab

Topics

• Antibodies, Monoclonal (chemistry, metabolism)
• Antibodies, Monoclonal, Humanized
• Avidin (chemistry, metabolism)
• Biotinylation
• Boron Compounds (chemistry, metabolism)
• Cetuximab
• ErbB Receptors (immunology)
• Flow Cytometry
• Fluorescent Dyes (chemistry, metabolism)
• Humans
• Immunoconjugates (chemistry, metabolism)
• Microscopy, Fluorescence
• Peritoneal Neoplasms (immunology, metabolism, pathology, secondary)
• Sensitivity and Specificity